Linkage And Gwa Studies In Schizophrenia
Although commonly used genetic methods have successfully identified single genes that cause many rare genetic disorders, these approaches have been less successful in complex disorders like schizophrenia. Multiple disease-related genetic loci have been reported by genetic linkage studies and GWASs in schizophrenia , yet relatively few causative genes have been found.
Linkage studies have identified numerous regions that show evidence of linkage to schizophrenia. In a genome scan meta-analysis, Ng et al. found that only two regions, one on chromosome 5q and another near the chromosome two centromere , demonstrate suggestive evidence for linkage in all ethnicities, and limiting their analysis to samples of European ancestry only added one additional region with evidence of a suggestive linkage, chromosome 8p. Several other regions showed nominal evidence for linkage and several regions were nearly significant , but none achieved genome-wide significance . The limited statistical power of these linkage studies are likely related to the composition of their study samples. Given that schizophrenia is associated with social isolation and reduced reproductive fitness, large, multi generational families that are ideal for linkage studies are few and far in between.
Stranger Social And Intergroup Anxiety
Humans generally require social acceptance and thus sometimes dread the disapproval of others. Apprehension of being judged by others may cause anxiety in social environments.
Anxiety during social interactions, particularly between strangers, is common among young people. It may persist into adulthood and become social anxiety or social phobia. “” in small children is not considered a phobia. In adults, an excessive fear of other people is not a developmentally common stage it is called . According to Cutting, social phobics do not fear the crowd but the fact that they may be judged negatively.
varies in degree and severity. For some people, it is characterized by experiencing discomfort or awkwardness during physical social contact , while in other cases it can lead to a fear of interacting with unfamiliar people altogether. Those suffering from this condition may restrict their lifestyles to accommodate the anxiety, minimizing social interaction whenever possible. Social anxiety also forms a core aspect of certain personality disorders, including .
Protective Role Of Estrogen In Neuropsychiatric Illness
ASD, ADHD, schizophrenia, and impulsive behavior disorders are more prevalent in males than females, whereas bipolar disorder is equally common . We proposed that this sex difference in ASD is because of the fact that estrogen, a steroid hormone, can replace vitamin D hormone in activating the TPH2 gene, thus raising serotonin levels . Because estrogen significantly increases the expression level of TPH2 in the brain, serotonin levels would also be raised . Therefore, we posit that estrogen would also be protective against other neuropsychiatric illnesses. Consistent with this proposal, rats, mice, and humans all have higher tryptophan hydroxylase activity in females compared with males .
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Epa Inhibits Inflammation And Depression
The E2 series prostaglandins are hormone-like signaling molecules that play an important role in promoting inflammation, particularly by inducing the production of proinflammatory cytokines such as interleukins IL-6 and IL-1 and TNF . Inflammatory cytokines generated in the periphery are able to cross the blood-brain barrier and cause neuroinflammation. It has been shown that injecting endotoxin in people, which causes an immune response and the production of proinflammatory cytokines, results in depression and inhibition of verbal and nonverbal memory . Similarly, intravenous injection of the IFN- inflammatory cytokine causes depressive symptoms in people however, the depression is ameliorated with supplementation with a high dose of EPA . Furthermore, individuals with gene polymorphisms in serotonin-related genes have been shown to have an even higher risk of inflammation-induced depression resulting from intravenous injection of IFN- . Although the link between depression and inflammation has been made, no mechanism has been identified. We think it is likely that the depression that occurs as a consequence of inflammation results from the inhibition of serotonin release, because serotonin also plays an important role in mood. Because serotonin regulates a wide range of cognitive functions and social behaviors in addition to mood, inhibiting the inflammatory E2 series prostaglandins with EPA has very important serotonin-related therapeutic implications.
Serotonin Regulates Executive Function And Sensory Gating
Sensory gating, which is the ability of the brain to filter out extraneous sensory inputs, also depends on serotonin levels. Defects in sensory gating cause a sensory overload of irrelevant information resulting in cognitive fragmentation, which shares comorbidity with numerous psychopathological disorders . Acute tryptophan depletion in normal individuals results in impaired sensory gating, thus suggesting that serotonin plays an important role in this process . Defects in sensory gating may also affect executive function and decision-making. In general, the overall data support the concept that low serotonin levels lead to impairments in executive function and sensory gating.
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Clinical Features Of Schizophrenia
Schizophrenia affects about 1% of the worlds population, .
Symptoms of schizophrenia may include hallucinations and delusions . These symptoms are referred to as positive symptoms though they are not positive to the person experiencing them. These symptoms are attributed to an increased activity of the neurotransmitter dopamine in a certain region of the brain.
Withdrawal, lack of interest in things a person used to love, or loss of interest in self-care, such as not eating or showering, are commonly called negative symptoms of schizophrenia. Some of these symptoms are known to be associated with a reduction of the same neurotransmitter dopamine in the frontal region of the brain, affecting the ability to be motivated, display normal facial expressions, or to initiate an action. Cognitive impairment is another important set of symptoms including memory deficits and inability to plan or make decisions. Furthermore, patients suffering from schizophrenia often do not realize they are sick and resist being hospitalized or refuse medications that can help them. The lack of insight in schizophrenia is quite common in schizophrenia. Medications as well as counselling can help patients develop awareness that they do have a medical illness and that they should adhere to their medication in order to achieve remission and ultimately recovery.
About This Research Topic
Neuropsychiatric disorders such as schizophrenia, extrapyramidal disorders, Alzheimer’s disease and other unrelated dementias, represent a serious human, medical and socioeconomic burden. These diseases are often accompanied by impairments of cognitive function, e.g., thinking, decision-making, and learning …
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Wes Findings In Schizophrenia
As yet, the literature in this emerging field remains small but very exciting in its suggestion that WES will be productive in identifying rare variants that may be causative in schizophrenia. One approach to examine whether rare variants may be inherited includes the study of trios . This strategy has been successful in gene identification in other diseases, such as intellectual disability and autism . Both of these studies used exome sequencing of patientâparent trios to identify de novo mutations in a complex trait that is characterized by extreme genetic heterogeneity. Such family-based methods can be used to determine whether variants are more likely inherited or de novo, with de novo mutations more likely to be pathogenic if both parents are unaffected. In addition to single-nucleotide changes, small insertions or deletions can also be detected, and the impact on the predicted protein product can be assessed.
The Unbiased Prediction Of Grb Target Genes Identifies Potentially Overlooked Candidate Genes At Well
The final example is a locus that overlaps the gene for the dopamine D2 receptor the target of all licensed antipsychotic therapy drugs . The unpredictability of a patients response to antipsychotic therapy, and alternative roles of this locus have been under recent scrutiny . This locus overlaps a GRB containing both DRD2 and a neural cell adhesion molecule gene, NCAM1, shown in Fig. . NCAM1 has previously been implicated in a number of neuropsychiatric disorders, including schizophrenia , and our analysis identifies NCAM1 as another plausible target, despite not being categorized as a GRB target . When active, the predicted enhancer element in the schizophrenia-associated locus affects transcription of both DRD2 and NCAM1, with a more prominent effect on the transcription of the NCAM1 gene . This locus illustrates the risk of hypothesis-driven target gene search: once a gene, e.g. DRD2, expected to play a role in disease aetiology is identified, other putative targets in its vicinity may be overlooked.
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Imaging And Treating Inflammation In Psychiatric Illness
Imaging neuroinflammation in situ
Clinically, neuroinflammation imaging may prove to be crucial for identifying the subgroup of psychiatric patients with neuroinflammation who would be most likely to respond favorably to immunomodulatory therapies. Additionally, such imaging may allow clinicians to monitor neuroinflammation-related disease activity and its response to immune therapy in psychiatric patients. Imaging inflammation in the human brain has traditionally depended upon MRI or CT visualization of extravagated intravenous contrast agents, indicating localized breakdown of the BBB. Gadolinium-enhanced MRI occasionally demonstrates such breakdown in the limbic regions associated with emotional processing in patients with psychiatric disorders attributable to paraneoplastic or other encephalitides . To our knowledge, however, abnormal enhancement has never been demonstrated in any classical psychiatric disorder , despite functional and ultrastructural BBB abnormalities .
Whether or not subtler neuroinflammation can be visualized in vivo in classical psychiatric disorders remains unknown. One promising technique is positron emission tomography using radiotracers, such as C11-PK11195, which bind to the translocator protein, previously known as the peripheral benzodiazepine receptor, expressed by activated microglia .
Role of antiinflammatory drugs in psychiatric disorders
Other Neuropsychiatric Disorders And Neurological Diseases
There are only a few reports that suggested the existence of an association between the RELN and BP . Goes et al. found that the rs362719 of RELN was associated with susceptibility to BP, particularly in females.
Several groups have also reported an association between AD and the RELN gene . AD is a neurodegenerative disease characterized by the formation of neurofibrillary tangles and beta-amyloid plaques in the brain, and patients clinically manifest progressive impairments of memory and cognition . Several SNPs in the RELN gene have been reported to be associated with the risk of AD. Seripa et al. showed an association between a triplet tandem repeat in the 5UTR and rs607755 with AD, particularly in females. Another group also showed significant association between rs607755 and the risk of AD . However, their results were inconsistent with the conclusion by Seripa et al. that rs607755 was significantly associated with AD only in males . Antoniades et al. reported that an SNP in exon 22 of RELN was significantly associated with the risk of AD in a Greek population. Bufill et al. reported that SNPs in the RELN gene and two genes related to the Reelin signaling pathway were associated with AD and mild cognitive impairment .
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Epa Regulates Serotonin Release
We propose that one important mechanism by which omega-3 fatty acids modulate serotonin function is through regulation of serotonin release in the presynaptic neuron . Serotonin release is inhibited by the E2 series prostaglandins generated from arachidonic acid, an omega-6 fatty acid that is produced from linoleic acid in animals . EPA inhibits the formation of the E2 series prostaglandins, inhibiting the formation of arachidonic acid in both young and old individuals . In rats fed a diet high in arachidonic acid, E2 series prostaglandins were elevated in the hippocampus, which was attenuated by feeding the rats EPA . Because the E2 series prostaglandins inhibit serotonin release and EPA inhibits the generation of these prostaglandins, it seems likely that EPA in the brain would be important for normal serotonin release. Indeed, human plasma omega-3 levels have been positively correlated with the serotonin metabolite 5-HIAA in cerebral spinal fluid . Dietary surveys in the United States indicate that the average adult intakes of linoleic acid , -linolenic acid , EPA, and DHA are ~12-20, 1.4-2.0, 0.03-0.06, and 0.05-0.10 g/d, respectively . These data suggest that most adults are not getting enough EPA and DHA from their diet.
The Implications For Schizophrenia Of Wes On Intellectual Disability Research
WES has the potential to transform the investigation of the genetics of neuropsychiatry diseases like schizophrenia. For example, a recent study demonstrated the power of this method to identify novel mutations in a cohort with severe intellectual disability , another disorder that also exhibits substantial genetic heterogeneity. In this study, de novo mutations were found in 53 of 100 subjects. In 13 subjects, these mutations occurred in genes predicted to play a role in causing intellectual disability. Potentially causative mutations were identified in the novel candidate genes of 22 of these patients. For three of these patients, a second set of affected individuals revealed mutations in genes that were uncovered in the initial WES study, which strongly implicated DYNC1H1, GATAD2B, and CTNNB1 as novel genes causing intellectual disability. This type of work is rapidly advanced by the expanding publicly available databases of common human genetic polymorphisms, in which the allele frequencies generated from sequencing the genomes of several reference populations are readily available for comparison . This has been, to date, the most successful strategy for gene identification in rare Mendelian disorders.
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Vitamin D Regulates Serotonin
Vitamin D is first converted to 25-hydroxyvitamin D , which is the major stable circulating form of vitamin D, and then to the biologically active steroid hormone 1,25-dihydroxyvitamin D . We recently proposed an underlying mechanism that describes how vitamin D hormone, which appears to control > 900 genes, is a key regulator of brain serotonin synthesis through TPH2, which contains a VDRE consistent with activation . We identified 2 distinct VDREs present in the regulatory regions of both TPH2 and TPH1, the 2 genes responsible for the conversion of tryptophan into serotonin in the brain vs. other tissues, respectively . We proposed that the VDREs would respond to vitamin D hormone in an inverse mode, with TPH2 being transcriptionally activated in the brain and TPH1 repressed in tissues outside of the blood-brain barrier . This proposal was based on evidence that the VDRE sequence alone can determine whether vitamin D hormone will activate or repress gene transcription . New biochemical evidence validates our proposal by showing that vitamin D hormone activates TPH2 expression in cultured neuronal cells .
The Case For The Rapprochement Of Neurology And Psychiatry
Given the considerable overlap between these subspecialities, there has been a resurgence of interest and debate relating to neuropsychiatry in academia over the last decade.Most of this work argues for a rapprochement of neurology and psychiatry, forming a specialty above and beyond a subspecialty of psychiatry. For example, Professor Joseph B. Martin, former Dean of Harvard Medical School and a neurologist by training, has summarized the argument for reunion: “the separation of the two categories is arbitrary, often influenced by beliefs rather than proven scientific observations. And the fact that the brain and mind are one makes the separation artificial anyway.” These points and some of the other major arguments are detailed below.
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Genetic Liability Accounts For Some Schizophrenia Symptoms
Schizophrenia PRS was linked to increased disorganized symptom dimension scores.
New research sheds light on the genetic liability interplay that results in cognitive impairment and different symptom scores for patients with schizophrenia.
It is not currently known how variability in schizophrenia symptom dimensions and cognitive ability is linked with genetic liability for the disease.
A team based in the UK, led by Sophie E. Legge, PhD, MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, determined whether phenotypic dimensions within schizophrenia are associated with genetic liability to schizophrenia, other neuropsychiatric disorders, and overall intelligence.
A better understanding of the different factors underlying these symptom dimensions could contribute to the development of novel treatments for schizophrenia currently available treatments predominantly affect only positive symptoms, the authors wrote.
Associations Of Gut Microbiota And Metabolites With Neuropsychiatric Disorders
We found suggestive evidence of a protective effect of the host-genetic-driven increase in Blautia on the risk of AD . Importantly, we further observed suggestive evidence that genetically elevated gut metabolite GABA was associated with a lower risk of AD .
Fig. 1
Schematic representation of the present study, highlighting for each step of the study design and the significant results obtained. We aimed to estimate causal relationships between gut microbiota and neuropsychiatric disorders using a bi-directional Mendelian randomization approach . Then, we performed a two-sample MR analysis to identify which microbiota metabolites associated with these disorders . Finally, we identified 14 individual bacterial traits and 2 gut metabolites to be associated with these disorders. GABA, -aminobutyric acid SCFA, short-chain fatty acids
Sensitivity analysis yielded similar results for the causal effects of gut microbiota on neuropsychiatric disorders, and no horizontal pleiotropy or outliers were observed . No significant results were found for any of other selected gut microbiota or metabolites with neuropsychiatric disorders . MR power calculation showed strong power to detect significant causal effect for most of gut microbiota with the risk of AD, MDD, and SCZ, respectively .
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Neural Hyperexcitation Induces Immature
To examine the developmental changes in gene expression patterns in the rodent DG, we created a microarray dataset from postnatal day 8, 11, 14, 17, 21, 25, and 29 infant mice and compared it with a dataset from 33-week-old adult mice 12. Within the entire mice DG dataset, the largest overlap for changes in gene expression after pilocarpine injection was for the comparison between day 8 infant and 33-week-old adult mice . We included the dataset from postnatal day 8 infant mice for subsequent analysis. The expression levels of 6552 genes were increased in the DG of infant mice compared with adult mice, whereas the expression levels of 8637 genes were decreased . Next, we assessed the changes in gene expression induced by neural hyperexcitation in a rodent model. We obtained publicly available microarray datasets from the DG of adult rats after seizures induced by injection of pilocarpine 47. The expression levels of 7073 genes were significantly changed in the DG of epileptic-seizure rats 1 day after pilocarpine injection compared with rats treated with saline .